Narcotics typified by morphine (chemical name: 7,8-didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol) or a salt thereof have been clinically used for the purpose of easing postoperative pain or cancer pain since a long time ago. Recently, improvement of patients' QOL has become of importance and pain palliative medicine (palliative care) has been promoted, leading to significant increase in the used amount of narcotics.
In “Cancer Pain Relief” published by the World Health Organization in 1986, the following five points are listed as five basic rules in cancer pain treatment:
(1) by the mouth;
(2) by the clock;
(3) by the ladder;
(4) for the individual; and
(5) with attention to detail.
The reason why “(1) by the mouth” is stated is that, at the time of publication, oral administration was the most excellent in terms of patients' QOL among the administration methods of analgesics. As for other administration methods, for example, rectal administration has problems in that it is difficult to carry out the method for patients with diarrhea, melena or stoma, and also it is difficult to give a large dose. In addition, although sustained subcutaneous infusion or sustained intravenous infusion has an advantage in that the infusion rate is easy to control, the activity of patients is restricted and therefore, QOL is remarkably poor. Accordingly, oral administration is commonly used as the first choice.
In actuality, however, it often becomes difficult for cancer patients particularly in the end stages to orally take a drug, and there is no other choice but to choose rectal administration, sustained subcutaneous infusion or sustained intravenous infusion which is inferior from the viewpoint of the above-mentioned QOL. Therefore, a novel administration route capable of providing better QOL to patients has been explored.
As means for solving this problem, there is a transdermal therapeutic system (TTS) for systemically administering a drug through the skin. This TTS has a lot of advantages as compared with oral administration in that (1) the blood concentration can be maintained constant over a long period of time; (2) a first-pass effect in the liver can be avoided; (3) side effects on the gastrointestinal tract can be reduced; (4) administration to patients with difficulty in swallowing such as small children or elder people can be performed; (5) even in the case where side effects are developed, administration can be easily discontinued by detaching the system, and the like. Therefore, the development of the system has been actively carried out recently.
In Japan, a sustained transdermal absorption therapeutic agent for cancer pain containing fentanyl (trade name “Durotep Patch”) placed on the market in 2001 is a product that solves the above problem to a certain degree by employing this TTS.
Fentanyl generally has an advantage of having less side effects such as constipation, nausea or dizziness than morphine or a salt thereof, and, this is considered to be attributable to the fact that morphine or a salt thereof has a different mechanism of action from that of fentanyl. Specifically, the drugs are both μ receptor agonists, but μ receptor is classified into two subtypes in mice: μ1 receptor involved in expression of physical dependence such as leaps and shudders; and μ2 receptor involved in expression of physical dependence such as diarrhea and body weight loss and mental dependence. It is known that fentanyl has a relatively higher selectivity for the μ1 receptor than morphine and the pharmacological action of fentanyl via the μ2 receptor is considered to be weak also in humans. Accordingly, this does not eliminate the need for morphine.
Further, although the number of such cases is relatively few, cases have been reported in which symptoms considered to be withdrawal symptoms caused by physical dependence of morphine were developed when a drug was changed from morphine or a salt thereof to fentanyl (Non-patent document 1). This is one of the reasons why doctors hesitate about switching to fentanyl. As described above, fentanyl cannot serve as a complete alternative drug to morphine.
Accordingly, if there is a preparation with which transdermally administering an effective amount of morphine or a salt thereof in a sustained manner becomes capable, the above-mentioned problems are all solved, and thus, such a preparation has been demanded. However, morphine or a salt thereof is a drug having a property of extremely low skin permeability, and therefore, the development of such a preparation was very difficult.
An attempt to formulate morphine or a salt thereof or a substance related thereto into a transdermal or transmucosal absorption preparation has been made since a long time ago. For example, techniques as described below have been known.
That is, a method for transnasal delivery of morphine gluconate is disclosed in Patent document 1; a transdermal absorption accelerator selected from terpenes and essential oils, a transdermal absorption accelerator aid comprising a lower alcohol and water or a lower glycol, and an aqueous or lower glycol-based transdermal absorption composition containing a salt of morphine are disclosed in Patent document 2; and a composition obtained by blending a narcotic analgesic in a base containing a lower alcohol, a polar solvent and an azacyclo alkane derivative is disclosed in Patent document 3.
Further, an external preparation of a morphine-type compound with the addition of a medium-chain fatty acid monoglyceride in an amount of from 50 to 99.95% by weight of the total weight of the preparation is disclosed in Patent document 4; a local composition for transdermal delivery of a prodrug derivative of morphine is disclosed in Patent document 5; a transdermal absorption preparation comprising a support and, laminated thereon, an adhesive, a transdermal absorption accelerator selected from the group consisting of hydroxycarboxylic acids and dicarboxylic acids having 2 to 8 carbon atoms and a base containing crospovidone and morphine hydrochloride or morphine sulfate is disclosed in Patent document 6; an ointment containing a morphine, a medium-chain fatty acid monoglyceride and a long-chain saturated fatty acid glyceride is disclosed in Patent document 7; and a transdermal device suitable for continuous administration of an opiate/opioid analgesic over a period of about 24 to 144 hours via a region of the skin from which the epidermis has been removed is disclosed in Patent document 8.
Further, a transdermal absorption patch comprising a support and, provided thereon, an adhesive layer containing an adhesive, an acid addition salt of morphine and a transdermal absorption accelerator, wherein the transdermal absorption accelerator is (A) a compound having a log P value (P denotes a partition coefficient in an octanol-water system) of from −0.5 to 2.0, (B) an oxycarboxylic acid having 2 to 8 carbon atoms and/or a dicarboxylic acid having 2 to 8 carbon atoms, and (C) a compound selected from the group consisting of fatty acid amides which are reaction products of an aliphatic monocarboxylic acid having 10 to 14 carbon atoms with a mono- or diethanolamine, acyl sarcosines and alkyl hydroxybenzoates having an alkyl group with 1 to 5 carbon atoms is disclosed in Patent document 9; and a transdermal absorption patch comprising a support and, provided on one surface thereof, an adhesive layer containing an adhesive, a drug, an adhesion-imparting agent and a transdermal absorption accelerator, wherein the drug is an acid addition salt of morphine, and the adhesion-imparting agent is a hydrogenated rosin glycerin ester, and the transdermal absorption accelerator contains (A) an organic compound having a log P value (P denotes a partition coefficient in an octanol-water system) of from −0.5 to 2.0, and/or (B) an oxycarboxylic acid having 2 to 8 carbon atoms and/or a dicarboxylic acid having 2 to 8 carbon atoms is disclosed in Patent document 10.
Further, an aqueous transdermal absorption preparation characterized by incorporating morphine hydrochloride uniformly in a base microemulsion containing a monoester or a diester composed of propylene glycol and a medium-chain fatty acid, a medium-chain fatty acid monoglyceride, a surfactant and water is disclosed in Patent document 11; a patch obtained by blending morphine, an acrylic adhesive and triacetin is disclosed in Patent document 12; and an ointment containing morphine and an effective amount of one of or a complex of two or more of phosphate derivatives of a lipophilic and pharmaceutically acceptable compound is disclosed in Patent document 13.
However, all these have problems in that (1) the blood concentration of the active ingredient or the skin permeation rate of the active ingredient obtained in the experiment is low and when the data is extrapolated to humans, the probability that the blood concentration does not reach an effective blood concentration is high; (2) a ratio of the applied area to the body surface area in the experiment is significantly high and when the data is extrapolated to humans, the probability that the size exceeds a practically applicable preparation size is high; (3) the duration of action is extremely short (less than 24 hours), and the like, and are not satisfactory as means for solving the above-mentioned problems, and practically, there has been no preparation capable of transdermally administering morphine or a salt thereof in a sustained manner in the market.
Patent document 1: JP-T-2003-501446
Patent document 2: Japanese Patent No. 2669951
Patent document 3: Japanese Patent No. 2843923
Patent document 4: Japanese Patent No. 2775053
Patent document 5: Japanese Patent No. 3493434
Patent document 6: Japanese Patent No. 3280711
Patent document 7: Japanese Patent No. 3514480
Patent document 8: JP-T-2000-507241
Patent document 9: JP-A-H07-300418
Patent document 10: JP-A-H08-143458
Patent document 11: JP-A-2001-151668
Patent document 12: JP-A-2001-039865
Patent document 13: JP-T-2005-537299
Non-patent document 1: Pain Med. 2006 March-April; 7(2):164-5